JP2006510613A - Liquid pharmaceutical composition containing 3,7-diazabicyclo [3.3.1] nonane compound and method for treating antiarrhythmic events - Google Patents

Abstract

The present invention relates to 3,7-diazabicyclo [3.3.1] nonane compounds, preferably 9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compounds, and most preferably tedisamil, and With regard to the use of the physiologically tolerable acid addition salts and / or solvates, preferably for the treatment and / or prevention of antiarrhythmic events in human patients, preferably atrial fibrillation (Afib) or crude It relates to the use in the form of a liquid pharmaceutical composition in the conversion of recent movements of movement into normal sinus rhythm (NSR). Furthermore, the present invention relates to therapeutic methods and pharmaceutical products.

Description

  The present invention relates to 3,7-diazabicyclo [3.3.1] nonane compounds, preferably 9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compounds, and most preferably tedisamil, and With regard to the use of the physiologically tolerable acid addition salts and / or solvates, preferably for the treatment and / or prevention of antiarrhythmic events in human patients, preferably atrial fibrillation (Afib) or crude It relates to the use in the form of a liquid pharmaceutical composition in the conversion of recent movements of movement into normal sinus rhythm (NSR). Furthermore, the present invention relates to therapeutic methods and pharmaceutical products.

  The 9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compound of formula I and its pharmacological activity are described in published European patent EP 103833 and the corresponding US patent 4550112, and Finnish patent FI 76338. It is known. The compounds of formula I are a subgroup of the 9,9-N, N'-tetrasubstituted 3,7-diazabicyclo [3.3.1] nonane compounds described in said patent specification and described therein Can be manufactured by the method described above. Said patent specification discloses that the compounds have generally useful cardioactive properties, particularly oxygen-sparing effects and effects on heart rate and heart rhythm, and are superior to high physiological tolerance. Thus, this compound exhibits sufficient antiarrhythmic action even at low doses. Furthermore, the undesirable negative effects on cardiac contractility are significantly lower; that is, the compound has a particularly advantageous ratio of antiarrhythmic activity or prolonged cardiac refractory activity to negative muscle inotropic secondary activity. .

  In addition, Burow et al. Also describe in US Pat. No. 5,164,401 that this compound has a clear diuretic effect with an advantageous excretion ratio between sodium and potassium.

  Furthermore, special salts of 3,7-diazabicyclo [3.3.1] nonane compounds, in particular 9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compounds and their preparation are described in US Pat. No. 5,324,732. ing. Thus, US Pat. No. 5,324,732 describes the fumarate salt of the compound containing 1.5 moles of fumaric acid per mole of the compound.

  Atrial fibrillation (AFib) is the most common persistent cardiac arrhythmia requiring hospitalization and affects millions of people worldwide. The prevalence of AFib increases with age and structural heart disease, as well as slightly more in men than in women. AFib is associated with significant mortality and morbidity and has a significant impact on quality of life. Restoring normal sinus rhythm (NSR) in patients with this arrhythmia improves hemodynamic conditions, reduces symptoms, and possibly reduces the risk of embolism. This can be achieved using DC cardioversion, but this technique has limitations such as the need for general anesthesia and hospitalization. Pharmacological transformations have therefore been proposed as an attractive alternative; various antiarrhythmic agents are being tested for this purpose. However, many of these agents have significant side effects such as potential for prearrhythmia, impaired LV function, or extracardiac effects that are not needed. Therefore, there is a need for the development of new antiarrhythmic agents that not only have good clinical effects but also have a favorable safety profile.

Tedisamil is a novel class III antiarrhythmic agent that blocks multiple potassium channels and slows sinus rate. This prolongs both the atrial and ventricular action potential periods in blocking transient extroversion I _to , ATP-dependent I _K-ATP and delayed regulated potassium flow I _Kr , I _Ks and I _Ku . Tedisamil extends the action potential period more strongly in the atria than in the ventricles. Unlike other selective potassium channel blocking agents, tedisamil does not show a reverse rate-dependent effect on ventricular refractory, which is away from the tendency to become prearrhythmic. Ultimately, tedisamil clearly has anti-anginal and anti-ischemic properties. Prediction, randomization, and controlled trials evaluated the efficacy and safety of rapid conversion of AFib or AFlu.

  The object of the present invention is to provide new pharmaceutical compositions and new medical treatments for human patients in need of treatment and / or prevention of antiarrhythmic events.

  Another object of the present invention is to provide a novel antiarrhythmic pharmaceutical composition having improved effects in human patients in need of treatment and / or prevention of antiarrhythmic events. The other subject of this invention is providing the pharmaceutical product relevant to the said subject.

  The subject of the present invention is a 3,7-diazabicyclo [3.3.1] nonane compound, preferably a 9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compound, and most preferably tedisamil. And the known useful pharmacological properties of physiologically tolerable acid addition salts and / or solvates and / or prodrugs of these compounds, particularly in the treatment and / or prevention of antiarrhythmic events in human patients , Preferably in the conversion of recent onset of atrial fibrillation (Afib) or flutter in human patients to normal sinus rhythm (NSR), as a liquid composition, complete single dose and / or continuous dose Instead, it was achieved by surprisingly finding that it could be further enhanced when administered by a special route or schedule. According to a further aspect according to the invention, this object is directed to the use of at least one antiarrhythmic active 3,7-diazabicyclo [3.3.1] nonane compound as described in the present invention for antiarrhythmia in human patients. It is achieved by providing antiarrhythmic liquid pharmaceutical compositions, therapeutic methods, and methods and pharmaceutical formulations that are adapted or suitable for a particular and inventive route of administration or regimen containing in an effective amount.

  The subject of the present invention is therefore the treatment of at least one 3,7-diazabicyclo [3.3.1] nonane compound, at least its physiologically acceptable acid addition salt and / or solvate and / or prodrug. For the treatment and / or prevention of an antiarrhythmic event in a human patient, containing an effective amount, preferably to the normal sinus rhythm (NSR) of a recent onset of atrial fibrillation (Afib) or flutter in a human patient Liquid pharmaceutical composition in conversion, suitable for staged administration, totally discontinuous administration and / or optionally only partly continuous administration, preferably two continuous administration phases A liquid pharmaceutical composition that is suitable for a two-stage administration.

  In particular, the subject of the present invention relates to a liquid pharmaceutical composition, which is intended for infusion administration, preferably for gradual infusion administration, optionally with each stage being partly continuous infusion administration. Yes, advantageously suitable for two-stage infusion administration of two consecutive infusion administration phases.

  The term “liquid” refers to a 3,7-diazabicyclo [3.3.1] nonane compound, its physiologically acceptable acid addition salt and / or solvate and / or suitable for administration to human patients. Or any liquid form of a prodrug. Thus, the liquid composition may be a solution, an emulsion including microemulsions and nanoemulsions or a suspension including microsuspensions or nanosuspensions. The term “stepwise and / or totally discontinuous” means that the liquid composition according to the invention is administered completely in a single and / or continuous phase, or completely in a single and / or continuous regimen. Rather, it means to administer in one stage having at least two phases with separate dosage regimens, or in at least two stages having separate dosage regimens. Each phase and stage itself may be continuous or only partially continuous. Most advantageously, each phase or stage is continuous.

  In a pharmaceutical composition for the treatment and / or prevention of an antiarrhythmic event in a human patient, preferably in the conversion of a human patient's atrial fibrillation (Afib) or flutter to the recent sinus rhythm (NSR) The 3,7-diazabicyclo [3.3.1] nonane compounds that can be used according to the present invention, and the physiologically tolerable acid addition salts and / or solvates and / or prodrugs of these compounds have the formula I:

［式中、
Ｒ1は炭素原子１〜６個を有するアルキル基、窒素原子に直接結合していない二重結合を有する、炭素原子３〜６個を有するアルキレン基、炭素原子４〜９個を有するシクロアルキルアルキル基またはベンジル基を表し、
Ｒ2は低級アルキル基を表し、かつＲ3は低級アルキル基を表すか、または
Ｒ2およびＲ3は一緒になって炭素原子３〜６個を有するアルキレン鎖を形成し、かつ
Ｒ4は炭素原子１〜６個を有するアルキル基、窒素原子に直接結合していない二重結合を有する、炭素原子３〜６個を有するアルケニレン基、炭素原子４〜９個を有するシクロアルキルアルキル基、式ａ：

[Where:
R1 is an alkyl group having 1 to 6 carbon atoms, a double bond not directly bonded to a nitrogen atom, an alkylene group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 4 to 9 carbon atoms Or represents a benzyl group,
R2 represents a lower alkyl group and R3 represents a lower alkyl group, or R2 and R3 together form an alkylene chain having 3 to 6 carbon atoms, and R4 is 1 to 6 carbon atoms An alkenylene group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 4 to 9 carbon atoms, a double bond not directly bonded to the nitrogen atom, a formula a:

（ここで、Ｒ5は水素、ハロゲン、低級アルキルまたは低級アルコキシ基を表し、かつ
Ｚは炭素原子１〜３個を有するアルキレン鎖を表すかまたはフェニレン基と共役結合している二重結合を有するプロペニレン鎖を表す）に相当する基、または式ｂ：

(Wherein R5 represents a hydrogen, halogen, lower alkyl or lower alkoxy group, and Z represents an alkylene chain having 1 to 3 carbon atoms, or a propenylene having a double bond conjugated to a phenylene group. Or a group corresponding to formula b:

（ここで、Ｒ6は水素、ハロゲン、低級アルキルまたは低級アルコキシ基を表し、かつ
Ｒ7は水素、ハロゲン、低級アルキルまたは低級アルコキシ基を表す）に相当する基を表す］に相当する３,７−ジアザビシクロ［３.３.１］ノナン化合物、またはこれらの化合物の生理学的に認容性の酸付加塩および／または溶媒化合物である。

(Wherein R6 represents a hydrogen, halogen, lower alkyl or lower alkoxy group, and R7 represents a hydrogen, halogen, lower alkyl or lower alkoxy group) or a 3,7-diazabicyclo group corresponding to [3.3.1] Nonane compounds, or physiologically tolerable acid addition salts and / or solvates of these compounds.

  Particularly advantageous compounds according to the invention are those compounds of the formula I in which R 1 represents an alkyl group having 1 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms. In further preferred compounds of the formula I, the substituent R 4 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkylalkyl group having 4 to 7 carbon atoms or a group corresponding to formula b.

  Preferred compounds according to the invention are those in which R1 represents an alkyl group having 3 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms, and R4 is an alkyl having 3 to 6 carbon atoms. A compound of formula I representing a group or a cycloalkylalkyl group having 4 to 7 carbon atoms. The 3,7-diazabicyclo [3.3.1] nonane compound forms an alkylene chain in which R 2 and R 3 in Formula I together have 4 to 5 carbon atoms, and R 1 and R 4 are independent of each other A 9,9-alkylene-3,7-diazabicyclo [3.3.1] of the formula I representing a straight-chain or branched alkyl group having 3 to 4 carbon atoms or a cyclopropylmethyl group Nonane compounds, and physiologically acceptable acid addition salts and / or solvates thereof. Preferred salts for this group of compounds are the fumarate salts of 9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compounds having 1.5 mol of fumaric acid per mole of compound of formula I. It is.

  Further preferred compounds according to the invention are N, N′-dicyclopropyl-methyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane (tedisamyl), N-isobutyl-N A compound selected from the group consisting of '-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3.3.1] nonane and physiologically acceptable acid addition salts and / or solvates thereof. is there. Preferred salts of this group of compounds are those of N, N'-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane (tedisamil) or N-isobutyl- N'-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3.3.1] nonane compound is the 9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compound 1 described above. It is a fumarate containing 1.5 moles of fumaric acid per mole.

  Alternatively, the hydrochloride salt is likewise very suitable in the present invention as an acid addition salt of a 3,7-diazabicyclo [3.3.1] nonane compound.

  Particularly preferred 3,7-diazabicyclo [3.3.1] nonane compounds are 9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compounds, tedisamil and physiologically acceptable acid additions thereof. Salts and / or solvates and / or prodrugs. These are most advantageously used as compounds in liquid pharmaceutical compositions. If a tedisamil acid addition salt is used, it is advantageously used according to the invention in the form of tedisamil hydrochloride or tedisamil sesquifumarate. Other pharmacologically acceptable acid addition salts of tedisamil are known from European Patent 103833. Thus, inorganic acids such as sulfuric acid or hydrohalic acids, in particular hydrochloric acid; or organic acids such as lower aliphatic monocarboxylic acids or dicarboxylic acids such as acetic acid, fumaric acid, tartaric acid, lactic acid, maleic acid, citric acid or salicylic acid Or a salt with, for example, a lower alkyl sulfonic acid such as methane sulfonic acid, or a benzene sulfonic acid optionally substituted on the benzene ring with halogen or lower alkyl, such as p-toluene sulfonic acid. Suitable as physiologically tolerable acid addition salts of the compounds of I.

  Surprisingly, the 3,7,9,9-tetra-substituted 3,7-diazabicyclo [3.3.1] nonane compound corresponding to Formula I is prepared as a liquid pharmaceutical composition in a step-wise, total In a non-continuous and / or optionally only partially continuous administration, especially as a two-stage administration of two consecutive administration phases, more specifically in the schedule according to the invention as illustrated below In particular, when administered as an infusion method, in addition to the known general cardioactive properties already mentioned above, in human patients with antiarrhythmia, particularly recent atrial fibrillation (Afib) or flutter in human patients It has been found that a markedly enhanced effect is superior in the conversion of pathogenesis to normal sinus rhythm (NSR).

  For example, a liquid pharmaceutical composition according to the present invention comprises a first of a 3,7-diazabicyclo [3.3.1] nonane compound, a physiologically acceptable acid addition salt and / or a solvate and / or a prodrug thereof. It may contain a therapeutically effective amount, which is sufficient for the treatment and / or prevention of antiarrhythmic events in human patients, which is about 10 ± 2 minutes, preferably about 10 ± 1 minutes, most Advantageously administered over a first time period of about 10 ± 0.5 minutes, and then 3,7-diazabicyclo [3.3.1] nonane compound, a physiologically tolerated acid addition salt thereof and / or It may contain a second therapeutically effective amount of the solvate and / or prodrug, which is sufficient to continue treatment and / or prevention, which is about 20 ± 5 minutes, preferably about 20 ± 3 minutes. , Most advantageously about 0 administered over a second time period of ± 1 minute.

  A further embodiment of the invention is a pharmaceutical product. Accordingly, the present invention provides, as described above, at least one 3,7-diazabicyclo [3.3.1] nonane compound, at least one physiologically acceptable acid addition salt and / or solvate thereof and / or Or a therapeutically effective amount of a prodrug is included as a drug in a liquid pharmaceutical composition and the 3,7-diazabicyclo [3.3.1] nonane compound is stepwise, totally discontinuous and / or A pharmaceutical product containing a label, a leaflet and / or a package charge which indicates that it can be administered only partly continuously, preferably for a two-stage administration of two consecutive administration phases And / or package. Such a pharmaceutical product and / or package according to the present invention may be a label, a leaflet and / or a package charge, a liquid pharmaceutical composition, optionally for infusion administration, preferably for gradual infusion administration. It is characterized in that it outlines that each stage is partly a continuous infusion administration, preferably suitable for a two-stage infusion administration in a two-continuous infusion administration phase. In particular, in embodiments of the invention, the pharmaceutical product and / or package is a label, leaflet and / or package charge, and the liquid pharmaceutical composition is 3,7-diazabicyclo [3.3.1]. A first therapeutically effective amount of a nonane compound, a physiologically acceptable acid addition salt thereof and / or a solvate and / or a prodrug that is sufficient for the treatment and / or prevention of an antiarrhythmic event in a human patient. Which is administered over a first time period of about 10 ± 2 minutes, preferably about 10 ± 1 minutes, most preferably about 10 ± 0.5 minutes, and the 3,7-diazabicyclo [ 3.3.1] a second that is sufficient to continue treatment and / or prevention of a nonane compound, its physiologically tolerable acid addition salt and / or solvate and / or prodrug A therapeutically effective amount, which is administered according to a dosage regimen of about 3,0-5 minutes, preferably about 20 ± 3 minutes, most preferably over a second time zone of about 20 ± 1 minutes. It is characterized in that it outlines that diazabicyclo [3.3.1] nonane compounds can be administered. The pharmaceutical product and / or package according to this embodiment of the invention comprises, as described above, at least one 3,7-diazabicyclo [3.3.1] nonane compound, a physiologically acceptable acid addition salt thereof and Advantageously, a therapeutically effective amount of the solvate and / or prodrug is contained as a drug in the liquid pharmaceutical composition.

  In a further embodiment, the present invention relates to therapeutic and / or prophylactic methods. Accordingly, the present invention provides a method for the treatment and / or prevention of anti-arrhythmic events in human patients, preferably the conversion of recent atrial fibrillation (Afib) or flutter in human patients to normal sinus rhythm (NSR). In which at least one 3,7-diazabicyclo [3.3.1] nonane compound or a physiologically tolerated acid addition salt and / or solvate thereof and / or Alternatively, a liquid pharmaceutical composition containing a therapeutically effective amount of a prodrug is advantageously administered to the patient in a stepwise route, a totally discontinuous route and / or optionally only a partially continuous route. Is administered for two-stage administration in two consecutive administration phases. In particular, in this therapeutic and / or prophylactic method according to the present invention, 3,7-diazabicyclo [3.3.1] nonane compound, or a physiologically tolerated acid addition salt and / or solvate and / or prodrug thereof The liquid pharmaceutical composition containing a therapeutically effective amount of the above is administered by the infusion route, preferably by stepwise infusion, optionally each step is partly continuous infusion, and preferably in two continuous administration phases. Administered for phased administration. An advantageous treatment and / or prophylaxis according to the invention is characterized by administering a liquid pharmaceutical composition, which comprises a 3,7-diazabicyclo [3.3.1] nonane compound, its physiologically acceptable acid addition. Containing a first therapeutically effective amount of a salt and / or solvate and / or prodrug that is sufficient for the treatment and / or prevention of an antiarrhythmic event in a human patient, for about 10 ± 2 minutes, Preferably administered over a first time period of about 10 ± 1 minutes, most preferably about 10 ± 0.5 minutes, and this is a 3,7-diazabicyclo [3.3.1] nonane compound, its physiology Containing a second therapeutically effective amount sufficient to continue treatment and / or prevention of a pharmaceutically acceptable acid addition salt and / or solvate and / or prodrug, which is advantageous for about 20 ± 5 minutes, About 20 ± 3 minutes , Which comprises administering over most advantageously a second time period of approximately 20 ± 1 min. In this therapeutic and / or prophylactic method according to the present invention, as described in detail above, at least one 3,7-diazabicyclo [3.3.1] nonane compound, its physiologically tolerable acid addition. Advantageously, a therapeutically effective amount of salt and / or solvate and / or prodrug is administered.

  According to the most advantageous embodiment of the invention, it is for example suitable to administer the liquid pharmaceutical composition as a two-stage infusion method, with about 10 ± 2 minutes, preferably about 10 ± 1 minutes. Most advantageously over a first time period of about 10 ± 0.5 minutes, 3,7-diazabicyclo [3.3.1] nonane compound, physiologically tolerable acid addition salts and / or solvates thereof and Is sufficient to administer a first therapeutically effective amount of a prodrug that is sufficient for the treatment and / or prevention of an antiarrhythmic event in a human patient, and then to continue treatment and / or prevention A second therapeutically effective amount of the 7-diazabicyclo [3.3.1] nonane compound, its physiologically acceptable acid addition salt and / or solvate and / or prodrug is about 20 ± 5 minutes, preferably about 20 ± 3 minutes Administered over a second time period of preferably about 20 ± 1 minutes. For a given time zone, the most recommended dosages for the two phases or phases are illustrated in more detail below. It will be apparent, however, that one skilled in the art can modify this dosage regime to some extent if desired. Usually, the total amount of 3,7-diazabicyclo [3.3.1] nonane compound, preferably tedisamil or one of its salts, is about 0.16 mg / kg to about 0.64 mg / kg based on the amount of this base compound. It is in the range of kg. Examples of specific amounts to be administered in the preferred two-stage infusion method are 0.16 mg / kg, 0.24 mg / kg, 0.32 mg / kg, 0.48 mg / kg or 0.64 mg / kg within this range. kg. About half of this total amount (100% by weight) (eg 50 ± 5% by weight) is administered in the first time period, eg about 10 ± 2 minutes, and about half of the remaining amount (eg up to 100% by weight 50 ± 5% by weight) ) Is administered over a second time period, eg, about 20 ± 5 minutes. In a particular example of the invention, 0.32 mg / kg of tedisamil base is used, injecting half of the dose over 10 minutes and half over 20 minutes.

  In general, the invention can be administered to patients of all ages and / or both sexes. However, in a particular embodiment, the discovery of the present invention is also particularly suitable for the treatment and / or prevention of antiarrhythmic events in male patients, preferably male patients with atrial fibrillation (Afib) or coarse It is suitable for converting the recent onset of movement to normal sinus rhythm (NSR). For this reason, from this particular point of view, the present invention is advantageously used for the treatment and / or prevention of antiarrhythmic events in male patients, preferably the normal sinus of recent onset of atrial fibrillation (Afib) or flutter in male patients Particularly suitable for treatment and / or prevention in conversion to rhythm (NSR), wherein at least one 3,7-diazabicyclo [3.3.1] nonane compound or a physiologically tolerated compound thereof A liquid pharmaceutical composition containing a therapeutically effective amount of an acid addition salt and / or a solvate and / or a prodrug is administered to the male the patient in a stepwise route, an overall discontinuous route and / or optionally. It is most advantageous if it is administered only partly by a continuous route of administration, but as a two-stage administration of two consecutive administration phases. In this specification, the invention consists of a liquid pharmaceutical composition, which is suitable for gradual administration, totally discontinuous administration and / or possibly only partially continuous administration to male patients, however most Advantageously, it is most suitable for administration as a two-stage administration of two consecutive administration phases of a 3,7-diazabicyclo [3.3.1] nonane compound, for example preferably tedisamil and its acid addition salt. A further aspect of the embodiments of the invention relating to the treatment of male patients is that at least one 3,7-diazabicyclo [3.3.1] nonane compound, as described above, as a medicament in a liquid pharmaceutical composition. Containing a therapeutically effective amount of at least one physiologically acceptable acid addition salt and / or solvate and / or prodrug thereof, and said 3,7-diazabicyclo [3.3.1] nonane compound That it can be administered to male patients in stages, totally discontinuously and / or optionally only partially continuously, most advantageously as a two-stage administration of two consecutive administration phases Directed to pharmaceutical products and / or packages containing indicating labels, leaflets and / or package charges. The details described in the content of the above embodiments of the present invention also fully apply to the specific embodiments relating to the treatment and / or prevention of antiarrhythmia in male patients.

  The markedly superior antiarrhythmic effect of the compounds of formula I in human patients can be demonstrated by PK / PD modeling and has been demonstrated by clinical laboratory data. This clinical laboratory data is obtained as a liquid pharmaceutical composition when administered according to the present invention in a stepwise, totally discontinuous and / or possibly only partially continuous regimen. Diazabicyclo [3.3.1] nonane compounds, such as tedisamil, and acid addition salts thereof are preferably used for the treatment and / or prevention of antiarrhythmia in human patients, preferably for atrial fibrillation (Afib) or flutter in human patients. It demonstrates that the suitability and effectiveness have been remarkably enhanced due to the recent pathogenesis to normal sinus rhythm (NSR).

Development of a two-stage injection method for rapid conversion of recent onset of atrial fibrillation / coarse movement to normal sinus rhythm (NSR) using PK / PD modeling Background: Tedisamil (TEDI) ) Is a novel III antiarrhythmic agent, which blocks various potassium outward currents, such as transient outward currents IKur, Ito, IKr, IKs and IKATP, and prevents atrial fibrillation (AF) / arrhythmia (AFL) It is under development for rapid conversion of recent pathogenesis to normal sinus rhythm (NSR). Intravenous doses up to 0.24 mg / kg of TEDI base infused over 10 minutes did not cause any conversion in AF / AFL patients. A two-stage injection method was developed using the PK / PD model to enhance drug concentration / exposure at the site of effect. The PK / PD model was based on data from a single injection study. The three-compartment injection PK model and the effect compartment model with linear links give the best fit. The model for the PD effect is a simple linear model. Modeling results were tested in 18 healthy male subjects in a double-blind, placebo-controlled, randomized, two-period crossover study, using a two-step infusion method with 0.32 mg / kg TEDI base and administered Half of the volume was infused over 10 minutes and half of the dose over 20 minutes.

  Objective: The objective of the study was to evaluate safety and tolerability and to correlate TEDI plasma concentrations with QT, QTc and heart rate, and compare these results with simulation data.

  Methods and results: TEDI is safe and well tolerated. The expected PD effect, ie, QT and QTc interval prolongation and a clear decrease in heart rate, was observed over 2 hours. The PK and PD results were in close agreement with the simulation based on the single injection PK / PD model: the single injection based simulation was in the 95% confidence interval around the expected population mean of the test.

  Conclusion: The two-stage infusion method is a stepwise, totally discontinuous route of administration of a 3,7-diazabicyclo [3.3.1] nonane compound, such as tedisamil and its acid addition salt, as a liquid pharmaceutical composition. And / or, optionally if only partly on a continuous regimen, advantageously for the treatment and / or prevention of antiarrhythmic effects, preferably normal of recent onset of atrial fibrillation (Afib) or flutter It is advantageous to administer for conversion to sinus rhythm (NSR), which increases the time of exposure at the site of physiological effect.

  The following excerpt from the laboratory report describes further details of the illustrated two-stage injection method.

  Double-blind, placebo-controlled, randomized, single iv dose to assess safety, tolerability, pharmacodynamics and pharmacokinetics during and after two-stage infusion of tedisamil in healthy male subjects, A two-period crossover study was performed with the following drugs and doses: 0.4 mg / kg body weight of tedisamil dihydrochloride / kg body weight over 30 minutes.

the purpose:
1. Evaluate the safety and tolerability of tedisamil during and after a two-stage infusion regimen in healthy male subjects (injecting 0.4 mg / kg body weight over 30 minutes, half of the dose taking 10 minutes) And half of the dose is infused over the remaining 20 minutes).
2. Test correlation between plasma concentration of tedisamil and pharmacodynamic variables, QT, QTc and heart rate, calculated from RR interval, using PK / PD model, and these results from previous simulation tests Compare with the results obtained.

methodology:
This was a single center, double-blind, placebo-controlled, randomized, single iv dose, two-period crossover study. Subjects were randomly allocated to the treatment sequence Tedisamil-Placebo or Placebo-Tedisamil. Number of patients (planned, screened, randomized and analyzed): planned: 18 people, screened: 27 people, randomized: 18 people, and analyzed: 18 people, in PK / PD and safety analysis)
Diagnosis and key criteria for inclusion:
Subjects, they are included in the inspection only in the case of healthy men, the age (including both) from 18 to 40 years old, the body weight index (BMI) is 18kg ^{/ m 2} ~28kg ^/ m 2 met It was. Test substance and dose and administration mode: Tedisamil dihydrochloride; Concentration: 2 mg / ml; Dose: 0.4 mg / kg body weight infused over 30 minutes, half of the dose infused over 10 minutes And half of the dose was injected over the remaining 20 minutes.
Route: Intravenous administration.

Duration of treatment:
One day per period, at which time the infusion over the entire period of 30 minutes was administered. Both drug doses were separated by a one week washout period.

Evaluation criteria:
Effect / Pharmacodynamics:
A 12-lead ECG was performed at several time points to examine the pharmacodynamic effects (effects on QT and QTc) of tedisamil during and after injection. Maximum values and maximum increases were induced for QTc and QT, and minimum values and maximum decreases were induced for heart rate. AUC (0-24) for placebo corrected QTc and QT and AUC (0-24) and minimum for maximum and placebo corrected heart rate were calculated similarly.

safety:
Screening assessments include physical examination, ECG, HIV / hepatitis screening, blood pressure and heart rate measurements, clinical laboratory measurements, drug urine tests, alcohol breath tests and medical history. Follow-up assessments include physical examinations, ECG, blood pressure and heart rate measurements, clinical laboratory tests, and questions about adverse events and concurrent medications. Blood pressure, heart rate, and ECG were recorded during concurrent medication treatment with tedisamil. Adverse events and concurrent drug treatment were monitored during the study.

Pharmacokinetics:
Blood samples for measurement of tedisamil plasma concentrations were performed during intravenous testing and at several time points thereafter during both test periods. The following pharmacokinetic parameters were _{determined: AUC (0-inf),} AUT (0-t), C max, Tmax, t 1/2, λ z, V ss, CL, considering MRT and terminal half-life Number of data measurement points taken.

Statistical methods:
Pharmacodynamics:
Data from subjects who completed both study periods were found to be valid for pharmacodynamic / pharmacokinetic analysis.

  Descriptive statistics were performed on ECG intervals QT, QTc, RR, PR, QRS and on heart rate at treatment (Tedisamil, Placebo and “Tedisamil-Placebo”) and time points.

  Individual and average (arithmetic mean ± 1SD) time profiles for ECG interval and heart rate were shown graphically for both treatments.

  Separate (co) variance (only covariance for maximum and minimum values) analysis was performed on the derived parameters, ie maximum and maximum increase for QTc and QT, and minimum and maximum decrease for heart rate, This includes subject, treatment, order and duration as class effect (and individual pre-dose as a covariance). Estimates and 95% confidence intervals were constructed for the difference “Tedisamil-Placebo” using residual variance. Model assumptions were checked by visual inspection of residual plots. In addition, descriptive statistics were calculated for the parameters derived per treatment and the difference “Tedisamil-Placebo”.

  Descriptive statistics were calculated for placebo corrected QTc, QT and heart rate AUC (0-24) and placebo corrected maximum effect (maximum for QTc and QT and minimum heart rate). In addition, a 95% confidence interval was derived based on the normal distribution results.

safety:
Subjects who received study medication were found to be effective for safe evaluation.

  Urgent adverse events due to treatment, defined as any event that exacerbates or initiates any adverse event present at baseline after treatment with study medication, are summarized in the term “COSTART” for each treatment group . Each adverse event was evaluated for frequency of occurrence, duration, intensity, effect, outcome, and association with test drug administration. Adverse events were listed for each subject.

  A list of abnormal or over-range values for each subject was shown for vital signs, laboratory assays, and physical examination. Adverse events, blood pressure, heart rate and clinical laboratory data were analyzed descriptively and investigated to assess the safety of all randomized subjects. All clinical abnormalities were recorded.

Pharmacokinetics:
The geometric mean and corresponding 90% confidence intervals were calculated for AUC, AUT (0-t), CL, and _{Cmax for} the plasma concentration of tedisamil at each time point.

The arithmetic mean and corresponding 90% confidence intervals were calculated for the other variables (V _ss , λ _z , t _1/2 , MRT). T _max is described using minimum, median, maximum and frequency numbers. Individual and mean plasma concentration versus time curves were plotted using both linear or semi-log scales.

Pharmacodynamics / Pharmacokinetics A non-linear mixed effects model was used to characterize the pharmacokinetics and pharmacodynamics of tedisamil after two-stage injection. The population mean prediction profile and confidence limits over time were obtained from the predicted PK and PD generated for each subject.

The pharmacokinetic and pharmacodynamic model of tedisamil injection established in the previous single injection test has been demonstrated in three stages:
i) The optimal PK model for the single injection test data set was determined.
ii) Joint PK / PD analysis was achieved on an expanded data set in single injection test data.
iii) Simulation-based population mean PK / PD prediction profiles were compared to those based on single-injection studies.

  Outlier check was performed with the overall residual plot and with the observed versus expected plot.

PK / PD compartment model:
The PK model for plasma concentration, Cp, was a three-compartment constant infusion model. A sequential PK / PD effect-compartment linear link model was used as the model for observing PD effects on ECG parameters.

Population analysis:
NONMEM V was used for all pharmacokinetic modeling. The PK / PD linear link model was adapted to use SAS Macro NLINMIX for nonlinear models.

Summary and conclusions Effect results:
Pharmacodynamics:
Descriptive statistics for the derived parameters of QT, QTc interval and heart rate are summarized in Table A below.

  A summary of the analysis on the derived parameters of QT, QTc interval and heart rate for the tedisamil-placebo comparison is summarized in the following table:

  For maximum or minimum analysis, the pre-dose was considered as a covariate. Statistical analysis of the derived parameters showed a clear increase in QT and QTc intervals and a clear decrease in heart rate. Each of the comparisons was statistically significant (p <0.002).

  In addition to the analysis, placebo corrected derived ECG interval parameters were examined. The table below shows the mean, variation and matched 95% confidence intervals for the placebo corrected derived parameters.

  A clear increase in placebo-corrected QT and QTc intervals and a clear decrease in placebo-corrected heart rate were shown in the 95% confidence interval for maximum (QT and QTc) and minimum (heart rate) values.

  No obvious effect of tedisamil could be found in the AUC (0-24) value. This can be explained at a selected length of the interval. Tedisamil has a strong effect on QT and QTc intervals and heart rate in the first 2 hours after administration. In the AUC (0-24) thus considered, the teddy samyl effect was masked at selected intervals.

Safety results:
Overall, 7 AEs occurred in 6 subjects.
• Six AEs were observed in 5 subjects after treatment with tedisamil. All AEs were determined to be probably related to the test drug: injection site reaction (mild and moderate), pain at injection site (mild x2, moderate x1) and sensory abnormalities (mild).
• One AE occurred in one subject during placebo treatment: the injection site responded mildly, which is probably related to the test drug.

  Overall, a two-stage infusion with 0.4 mg tedisamil dihydrochloride per kg body weight was well tolerated. No clinically relevant findings were observed in hematology, clinical chemistry, urine analysis and vital signs parameters. Nevertheless, there is a slight increase in the arithmetic mean of systolic and diastolic blood pressure in the first 4 hours after administration in the Tedisamil group and a decrease in heart rate in the first hour after administration, and in the placebo There was little change. This result is consistent with the safety and tolerability results obtained in the initial examination.

Pharmacokinetic results:
Descriptive statistics for the main pharmacokinetic parameters are shown in Table D below.

The time of peak plasma concentration varies (T _max ) in the range of 5 to 75 minutes after the start of infusion, showing an average value of 12.5 minutes.

PK / PD modeling results The optimal pharmacokinetic model is a ternary constant injection model. The PK modeling and PK / PD modeling of this study were in close agreement with the simulation based on the single injection study PK / PD model. The mobility between subjects in the predicted plasma concentration of tedisamil was greater in this test than in the single injection test.

  Effect for infusion administration-Compartment PK / PD model provides the power for actual special predicted QT and QTc: between predicted tedisamil concentration and QT and QTc in the effect compartment (0.93 and 0.807 respectively) The correlation was higher than the correlation between the observed plasma concentration and uncorrected QT and QTc (0.696 and 0.513, respectively).

  The time lag between plasma concentration and maximum effect was smaller than that seen in a single infusion, but the difference was small.

Conclusion:
Tedisamil was safe and well tolerated by a two-step infusion of 0.4 mg of tedisamil dihydrochloride per kg body weight into healthy male subjects. The expected pharmacodynamic effects of tedisamil, namely prominent QT and QTc interval prolongation and a clear decrease in heart rate, were observed over 2 hours after dosing. PK analysis enables a three-component constant injection model to describe both single and two-stage injection pharmacokinetics, while PK / PD analysis is effective to describe both single and two-stage injection pharmacodynamics The compartment link model was validated. Simulations based on these models have good predictive values.

  The following summary report on the data from the clinical laboratory performed gives further details on the clinical efficacy showing the usefulness of the two-stage infusion.

  Effects of intravenous tedisamil administration in converting multicenter, double-blind, randomized, placebo-controlled sequential ascending dose group testing to rapid normal sinus rhythm in patients with atrial fibrillation or flutter and Conducted to evaluate safety.

Drug / Dose:
Tedisamil (0.4mg per kg body weight)
Tedisamil (0.6mg per kg body weight)
The placebo dose was administered as a 30 minute intravenous infusion.

1. Study design A multicenter study is a double-blind, randomized, placebo comparing the efficacy and safety of tedisamil treatment versus placebo in symptomatic patients with atrial fibrillation or flutter (> 3 hours and <48 hours) It was a controlled sequential ascending dose group test. The primary effect end point for this study was atrial fibrillation or flutter cessation (at least 60 seconds) within 2.5 hours after the start of the infusion.

  This test was graded for atrial fibrillation and atrial flutter and performed in two stages. Doses were given sequentially for provisional safety assessment, and each dose was compared to the placebo group.

  Subjects for enrollment in this study were screened from investigators' praxis and referral bases.

  Patients eligible by screening and baseline assessment are randomized to tedisamil or placebo in a sequential dose escalation approach. In the first stage, patients receive 0.4 mg / kg tedisamil / kg body weight or placebo over an infusion period of 30 minutes, with half of the dose infused in the first 10 minutes and half of the dose for the remaining 20 Infused over a minute. After the interim safety assessment, in the second stage, the patient receives tedisamil 0.6 mg / kg body weight or placebo in the same infusion regimen.

  The patient's heart rhythm was continuously monitored by telemetry for 24 hours after the start of test drug infusion. Digitalis and / or β-blockers or diltiazem were allowed for heart rate control during this study.

  Antiarrhythmic agents are only allowed 24 hours after the start of the infusion to avoid any potential drug interaction with tedisamil.

  If clinically indicated, the investigator may restore sinus rhythm with DC cardioversion, either directly following the infusion or at any time during the examination, according to the DC cardioversion step-up protocol. Is possible. However, DC cardioversion within 2.5 hours after the start of infusion was strongly prevented.

  The patient was released from telemetry 24 hours after the infusion, and safety follow-up had to be received until 28 days later. A 12-lead ECG (including a 60 second rhythm strip) and a 24-hour holter to determine clinical endpoint (conversion to normal sinus rhythm) is performed by the center according to standard guidelines.

  FIG. 1: A flowchart of the inspection is shown in FIG.

2. Study objective 2.1 Primary effect objective The primary objective of the study is to determine the percentage of patients who have converted to normal sinus rhythm (NSR) (at least 60 seconds) at any time within 2.5 hours after the start of infusion. It was to show the superiority of any dose of tedisamil over placebo in the termination of atrial fibrillation / coarse.

2.2 Secondary Effect Objectives The secondary effect objectives are:
Tedisamil for placebo is converted to normal sinus rhythm (at least 60 seconds) at any time within 2.5 hours after initiation of intravenous infusion, and in sinus rhythm up to 2.5 hours after initiation of intravenous infusion To determine the percentage of patients whose condition persists.
To determine the percentage of patients who converted Tedisamil to placebo to normal sinus rhythm (at least 60 seconds) at any time within 24 hours after the start of intravenous infusion.
Tedisamil for placebo is converted to normal sinus rhythm (at least 60 seconds) at any time within 24 hours after the start of intravenous infusion, and the condition in the sinus rhythm persists until 24 hours after the start of intravenous infusion Determine the percentage of patients.
Tedisamil for placebo is converted to normal sinus rhythm (at least 60 seconds) at any time within 2.5 hours after the start of intravenous infusion and status of sinus rhythm up to 24 hours after the start of intravenous infusion To determine the percentage of patients that survive.
• Measure the time for conversion after the start of tedisamil injection into the placebo.
To determine the dose-response and concentration-response correlation of tedisamil to placebo.

2.3 Safety Objectives Safety objectives: To determine the safety and tolerability of tedisamil against placebo.

3. Inclusion criteria and exclusion criteria 3.1 Inclusive consent was voluntarily signed before the inclusion criteria / screening study started and before the test drug was administered.
• Male or female, above 18 years of age.
• Patients with recorded (60 second rhythm strip) symptomatic atrial fibrillation or flutter (duration> 3 hours and <48 hours) that occur as the first episode or recurrent episodes at randomization. Atrial fibrillation or flutter is recurrent if manifestation of symptoms has been previously recorded and is either spontaneously terminated or well treated with drugs or direct-current (DC) cardioversion It is recognized as. When randomized, the patient must show atrial fibrillation or flutter.
Patients who are hemodynamically stable (supposed systolic blood pressure> 90 mmHg and diastolic blood pressure <105 mmHg).

3.2 Criteria for exclusion Patients should be excluded from testing for any of the following reasons.
A woman who is pregnant, lactating, or not using medically acceptable contraceptives,
All women with the possibility of pregnancy and delivery who have not been surgically contraceptive must be negatively recorded in the serum pregnancy test at the screening visit, and medically acceptable contraceptive methods (eg, fallopian tubes) Ligation, pregnancy control pills, or any barrier method) must be performed for at least 3 calendar months prior to randomization. Women of pregnancy and childbirth should not be intended to become pregnant during the test period,
Some hematological, immunological, respiratory, genitourinary, gastrointestinal, hepatic, renal, which may limit participation in the test or prevent test inertia Endocrinological, metabolic, nutritional, psychiatric, dermatological, connective tissue, musculoskeletal, malignant or related disease, evidence of allergy or surgery, history, physical examination And / or when it appears in a laboratory evaluation,
Clinical evidence of hyperthyroidism,
The indicated atrial or ventricular thrombus or valve hypertrophy during a transesophageal echocardiogram.
A history of cerebrovascular attacks within 6 months prior to randomization,
-NYHA functional class III, IV congestive heart failure,
Acute coronary syndrome at the time of randomization,
A known history of preventricular excitement and / or evidence from an electrocardiogram,
A history of life-threatening ventricular arrhythmias, including torsades de pointes,
Evidence of ECG evidence of second or third degree AV block,
A 12-lead ECG recorded ventricular rate <50 ppm or> 200 bpm,
-Myocardial infarction within 30 days before randomization,
-Cardiac surgery within 3 months before randomization,
・ Stent placement or PTCA within 30 days before randomization,
・ Congenital long-term QT syndrome,
-QT interval before randomization> 470 ms,
Plasma creatinine> 1.8 mg / dl,
Serum potassium <4.0 mEq / L,
・ Signs of digitalis poisoning,
-Concurrent treatment with antiarrhythmic agents (excluding digitalis, diltiazem or beta-blockers) with a half-life x 5 discontinuous failure prior to randomization,
Treatment with amiodarone within 3 months before randomization,
・ Participation in previous teddy-sam clinical tests
・ Participation in clinical examination and / or ingestion of the investigational drug within 4 weeks before the screening visit,
A history of drug abuse, including alcohol within one year of the screening visit,
• History of severe drug allergy or severe abnormal drug reaction.

4. Concurrent drug therapy Concurrent use of Class-I or Class-III antiarrhythmic agents is not permitted. Class-I or class-III antiarrhythmic agents should be interrupted for longer than a 5-fold elimination half-life before randomization. Aminodarone should be interrupted 3 months before randomization. Furthermore, verapamil and all potential PR prolonging drugs are not allowed. Permissible drugs include anticoagulants, warfarin and other coumarin derivatives, heparin, potassium-sparing diuretics (alone or in combination with other diuretics), beta-blockers (other than sotalol) ), Dihydropyridine calcium channel blockers, diltiazem, aspirin, digoxin and digitoxin.

5. Test product, dosage and mode of administration Tedisamil dihydrochloride, 0.4 mg / kg body weight, 0.6 mg / kg body weight was administered intravenously. The total infusion time was 30 minutes, where half of the dose was infused within 10 minutes and half of the dose was infused within the remaining 20 minutes. Matching placebo was administered intravenously.

6. Evaluation Criteria 6.1 Effects 6.1.1 Primary Effects Percentage of patients who converted to normal sinus rhythm (at least 60 seconds) at any time within 2.5 hours after the start of test drug infusion.

6.1.2 Secondary effects • Tedisamil for placebo is converted to normal sinus rhythm (at least 60 seconds) at any time within 2.5 hours after initiation of intravenous infusion and after initiation of intravenous infusion Percentage of patients whose condition in sinus rhythm persists up to 2.5 hours.
• Percentage of patients who converted Tedisamil to placebo to normal sinus rhythm (at least 60 seconds) at any time within 24 hours after the start of intravenous infusion.
Tedisamil for placebo is converted to normal sinus rhythm (at least 60 seconds) at any time within 24 hours after the start of intravenous infusion, and the condition in the sinus rhythm persists until 24 hours after the start of intravenous infusion Percentage of patients.
Tedisamil for placebo is converted to normal sinus rhythm (at least 60 seconds) at any time within 2.5 hours after the start of intravenous infusion and status of sinus rhythm up to 24 hours after the start of intravenous infusion Percentage of patients that survive.
Time for conversion after the start of tedisamil injection to placebo.
Tedisamil dose-response and concentration-response correlation to placebo.

6.2 Safety Safety was monitored for physical examination, ECG, 24-hour Holter monitoring, vital signs, laboratory evaluation and adverse events.

7. Statistical Methods Treatment patient samples were analyzed for effects. All tests were two-sided and p-values <0.05 were found significant. Differences in conversion percentages were compared among treatment groups using Pearson chi-square statistics. Safety analysis was performed on safety patient samples. The number and percentage of patients with adverse events were calculated for each treatment group using the MedDRA favorable period and body system. Descriptive statistics were summarized in the treatment group regarding changes from baseline in QT, heart rate and blood pressure.

8. Patient population 8.1 Number of patients Overall, 203 patients signed informed consent, 200 patients were randomized, and 20 patients did not receive study medication. The analysis was based on two samples, a safety sample and a treatment objective sample.

8.1.1 Safety Sample The safety sample included 180 patients: 61 in the placebo group, 65 in the Tedisamil 0.4 mg / kg group (from now on in the 0.4 mg group), and 0.6 mg of Tedisamil. 54 people in the / kg group (from now on, the 0.6 mg group).

8.1.2 Treatment Objective Samples Treatment objective samples included 175 patients: 59 in the placebo group, 63 in the 0.4 mg group, and 54 in the 0.6 mg group. Of the 180 patients randomized and drug tested, 5 patients had no effect measures (ECG and Holter) after the start of the infusion and had to be removed from the ITT sample.

9. Safety results 9.1 Demographics Overall, in this study, 62% of patients are male and 38% are female; mean age is 63 years (range 29-87 years). 45% of patients were being treated with β-blockers. Upon randomization, 81% of patients had atrial fibrillation and 19% had atrial flutter. 63% of patients had NYHA class I and 34% had NYHA class II congestive heart failure. The average duration of atrial fibrillation or flutter was 24 hours, and 63% of patients had atrial fibrillation or flutter as recurrent attacks. The average time from the first recorded atrial fibrillation or atrial flutter was 2.3 years. Demographic data showed that none of the differences between treatment groups was large enough for clinical relevance.

9.2 Primary effect parameters For patients with atrial fibrillation, the percentage of patients who converted to normal sinus rhythm at any time within 2.5 hours after the start of test drug infusion was 9% (N = 4) and 46% (N = 24) and 57% (N = 24) in the 0.4 mg group and 0.6 mg group, respectively. Treatment comparison to placebo was clearly statistically significant for both treatment groups (p <0.001).

  The percentage of patients who converted to normal sinus rhythm (at least 60 seconds) at any time within 2.5 hours after the start of test drug infusion for patients with atrial flutter is 0% in the placebo group; They were 11% and 27% in the 0.4 mg and 0.6 mg groups of tedisamil, respectively. The treatment comparison to placebo was clearly statistically significant for the tedisamil 0.6 mg dose group (p <0.044). The percentage of patients who converted to normal sinus rhythm at any time within 2.5 hours after the start of test drug infusion was 7% in the placebo group for patients with atrial fibrillation taking β-blockers (N = 1), and 52% (N = 14) and 60% (N = 12) in the 0.4 mg and 0.6 mg groups of tedisamil, respectively.

9.2 Secondary effect parameters The results for primary and secondary effect parameters are listed in Tables 1 and 2 below:

  Results from the present invention, for example, the results of tests controlled by randomized placebo, are effective in acute conversion of patients with intravenously administered tedisamil with atrial fibrillation or flutter up to a 48 hour period It shows that. A 46% conversion rate was observed at 0.4 mg / kg of tedisamil and a 57% conversion rate was observed at a dose of 0.6 mg / kg. There was a rapid onset of action with an average time to cardioversion of 35 minutes after the start of tedisamil administration.

10. Conclusions The results of the primary and secondary effect parameters show that in the rapid conversion of atrial fibrillation to normal sinus rhythm, both dose-dependent and placebo and tedisamil 0.4 mg / kg and tedisamil 0.6 mg / kg Statistically significant difference between Results for patients with atrial flutter were statistically significant for the high dose group.

  Overall, tedisamil administered as a two-stage infusion has been shown to be effective in converting atrial fibrillation or flutter to NSR. Tedisamil was well tolerated, no persistent polymorphic VT was observed, and all patients did not require DC cardioversion for the treatment of VT.

  A two-stage infusion method for rapid conversion of recently-onset atrial fibrillation / coarse fibrillation to normal sinus rhythm may be particularly advantageous in male patients.

A) Clinical laboratory stage II Analysis of the first test surprisingly showed gender differences in efficacy, eg male patients were higher conversion compared to female patients when treated with tedisamil Indicates the rate. Furthermore, male patients showed lower safety issues than female patients. Thus, when compared to female patients, tedisamil is unique in antiarrhythmic therapy and especially in male patients, particularly in the conversion of a recent onset of atrial fibrillation (Afib) to normal sinus rhythm (NSR) It was surprising that it was found to have.

  This initial laboratory test is a multicenter, double-blind, randomized to assess the efficacy and safety of intravenous tedisamil in rapid conversion to normal sinus rhythm in patients with atrial fibrillation or flutter And placebo control, sequential ascending dose group test. The active ingredient used was tedisamil dihydrochloride. This study was designed as a Phase II phase and performed at 35-40 centers in 3-4 countries. Examination period: screening: up to 48 hours; treatment (in patients): single 30 minute infusion; safety tracking: 24 hours (in patients) and 28 days safety tracking in continuous telemetry.

  The primary effect of the study should be to show the advantage of any dose of tedisamil over placebo at the end of atrial fibrillation / coarse movement, any time within 2.5 hours after the start of infusion At the percentage of patients converted to normal sinus rhythm (NSR) (at least 60 seconds). The purpose of the secondary effect was to determine the percentage of patients whose condition persisted in sinus rhythm 2.5 hours after the start of intravenous infusion of tedisamil to placebo; sinus 24 hours after initiating intravenous infusion of tedisamil to placebo Determining the percentage of patients whose condition persists in rhythm; Determining the time to convert after initiation of infusion of tedisamil against placebo; and Determining the dose-response and plasma concentration-response relationship of tedisamil against placebo thing. Safety Objective: To determine the safety and tolerability of tedisamil against placebo.

  The following methods were applied: multicenter, double-blind, randomized, placebo control, sequential ascending dose group tests were evaluated for the efficacy and safety of intravenous tedisamil vs. placebo. The test drug is infused over 30 minutes, with half of the dose received within 10 minutes and half of the dose received within the remaining 20 minutes. The first group of patients receives 0.4 mg / kg body weight (bw) but is infused with 0.2 mg / kg bw within 10 minutes and continues with an infusion of 0.2 mg / kg bw within 20 minutes. The next highest dose of 0.6 mg / kg bw (0.3 mg / kg bw infused within 10 minutes followed by 0.3 mg / kg bw infused within 20 minutes) was evaluated (blind) ) And administered only after it has been found to be safe. The third stage can administer higher doses. Tedisamil blood levels are assessed during infusion (at 10 and 30 minutes), at time of conversion to normal sinus rhythm, at time of relapse, and 24 hours after infusion.

  Planned number of subjects: 330 randomized (110 patients per dose group).

Diagnostic and main criteria for inclusion:
Atrial fibrillation and flutter with durations> 3 hours and <48 hours, occurring as first or recurrent attacks.

Product, dosage and method of administration:
・ Tedisamil (0.4mg / kg body weight)
・ Tedisamil (0.6mg / kg body weight)
Both doses are given intravenously for 30 minutes.

Control treatment, dosage and administration method:
Placebo (vehicle) is administered as a 30 minute intravenous infusion.

Duration of treatment The total infusion time is 30 minutes, with half of the dose being infused within 10 minutes and half of the dose being infused within the remaining 20 minutes.

Criteria for evaluation:
1) Effect:
Primary effect: Percentage of patients who converted to normal sinus rhythm (at least 60 seconds) at any time within 2.5 hours after the start of test drug infusion.

  Secondary effects: percentage of patients in NSR at 2.5 and 24 hours after the start of infusion; time for conversion; dose-response and concentration-response correlation.

2) Safety:
Physical examination, ECG, 24-hour Holter monitoring, vital signs, laboratory evaluation and adverse events.

Statistical methods:
All effect variables were evaluated separately for patients with atrial fibrillation and patients with atrial flutter. The percentage of conversion was compared between treatment groups using a theoretical regression model with treatment group and center factors. Time for conversion was a factor for the treatment group and center and was tested using the Cox proportional hazards model. Dose-response and concentration-response relationships were tested using descriptive statistics. The following assumptions were made for calculating the number of patients:
1. For patients with atrial fibrillation, the percentage of conversion to normal sinus rhythm in the placebo group (at any time within 2.5 hours after the start of the infusion) is equal to 20%, a clinically relevant difference Is 20%.
2. For patients with atrial flutter, the percentage of conversion to normal sinus rhythm in the placebo group is equal to 10% with a clinically relevant difference of 40%.

  A preliminary analysis of the effect was performed between the first and second stages by an external statistician. The goal is to terminate the stage when the tedisamil dose used in that stage is ineffective. Technically, each provisional analysis was a predictive ability calculation for the comparison of tedisamil and placebo with respect to the primary effect variable. A blinded safety review will be performed at the same time as an effect analysis and at the end of each stage (if appropriate).

B) Clinical Trial Stage III Analysis of the second test confirmed the discovery of the first test, i.e. showed differences in gender with respect to the effect, e.g. male patients were treated with female patients when treated with tedisamil Compared with higher conversion rate.

  The second laboratory test is a multicenter, two-way evaluation to evaluate the efficacy and safety of intravenous teddy samyl sesquifumarate in rapid conversion to normal sinus rhythm in subjects who have recently had atrial fibrillation or flutter. Double-blind, randomized, placebo control, parallel design inspection.

  The active ingredient used was teddy samil sesquifumarate. This study was designed as a Phase II study and was conducted at 30-40 centers in 5 countries. Examination period: screening: up to 48 hours; treatment (inpatient): single 30 minute infusion; safety follow-up: 24 hours (inpatient) and 28 days safety follow-up on continuous telemetry.

  The primary effect of the test is to show the advantage of any dose of tedisamil sesquifumarate over placebo in rapid conversion to normal sinus rhythm (NSR) (at least 60 seconds), when the infusion starts Measured in percentage of subjects done at any time within 2.5 hours later. The secondary effect was to convert tedisamil sesquifumarate to placebo to normal sinus rhythm at any time within 2.5 hours after the start of intravenous infusion and at 2.5 hours after the start of intravenous infusion. Determining the percentage in subjects with normal sinus rhythm; converting to normal sinus rhythm at any time within 2.5 hours after initiation of intravenous infusion of teddysamil sesquifumarate for placebo and intravenous infusion To determine the percentage of subjects with normal sinus rhythm 24 hours after the start of; conversion to normal sinus rhythm at any time within 2.5 hours after the start of intravenous infusion and normal sinus at discharge Determining the percentage of subjects that are rhythm; time to convert to normal sinus rhythm after initiation of intravenous infusion of teddysamil sesquifumarate for placebo Determining the dose-response relationship and concentration-response relationship of tedisamil sesquifumarate to placebo; determining the energy required for the DC cardioversion of tedisamil sesquifumarate to placebo Met. Safety Target: To determine the safety and tolerability of teddy samyl sesquifumarate for placebo.

The following methodology was applied: a multicenter, double-blind, randomized, placebo-controlled study was conducted to assess the efficacy and safety of teddysamil sesquifumarate on intravenous placebo. The test drug is infused over 30 minutes, with half of the dose received within 10 minutes and half of the dose received within the remaining 20 minutes. Subjects were randomly assigned to receive one of the following:
-0.32 mg tedisamil free base per kg body weight (bw) (0.16 mg / kg bw within 10 minutes, then 0.16 mg / kg bw within 20 minutes); or-0.48 mg tedisamil free base per kg body weight (bw) (0.24 mg / kg bw within 10 minutes, then 0.24 mg / kg bw within 20 minutes); or -0.64 mg tedisamil free base per kg body weight (bw) (0.32 mg / kg bw within 10 minutes, then 20 0.32 mg / kg bw within minutes); or-Placebo infusion for 30 minutes.

Planned number of people:
212 randomized atrial fibrillation subjects (53 subjects per treatment group). These subjects are the primary target population. In addition, it was considered that 80 subjects with atrial flutter (20 per treatment group) should be enrolled within the scope of this study. However, this test can be terminated without any atrial flutter subjects if the planned number of atrial fibrillation subjects has been reached.

Diagnosis for inclusion and primary criteria Atrial fibrillation or flutter with a period of> 3 hours to <45 days occurs as the first or recurrent attack.

Test product, dosage and administration method:
Test product, dosage and administration method:
-Tedisamil free base 0.32 mg / kg body weight (corresponding to tedisamil sesquifumarate 0.51 mg / kg and tedisamil dihydrochloride 0.4 mg / kg); or-tedisamil free base 0.48 mg / kg body weight Equivalent to 0.77 mg / kg of fumarate and 0.6 mg / kg of tedisamil dihydrochloride; or-0.64 mg / kg body weight of tedisamil free base (1.02 mg / kg of tedisamil sesquifumarate and 0.02 Equivalent to 8 mg / kg).

  These doses are administered as an intravenous administration method.

  The dose of tedisamil in the experimental report relates to tedisamil free base.

Control treatment, dosage and administration method:
Placebo (vehicle) is administered as an intravenous infusion for 30 minutes similar to tedisamil infusion.

Treatment period:
Total infusion time was 30 minutes: half of the dose was infused within 10 minutes and half was infused for the remaining 20 minutes.

Criteria for evaluation:
1) Effect:
Primary effect: Percentage of subjects who converted to normal sinus rhythm (at least 60 seconds) at any time within 2.5 hours after the start of test drug infusion.

  Secondary effects: Percentage of subjects within normal sinus rhythm, time for conversion, dose-response at any time within 2.5 hours after the start of infusion and at 24 hours and at discharge. Correlation and concentration-response correlation and DC cardioversion energy.

2) Safety:
Physical testing, ECG, 24-hour Holter monitoring, vital signs, laboratory evaluation and adverse events.

Statistical methods:
The percentage of conversion is compared between treatment groups using Pearson chi-square statistics. Time for conversion is compared between treatment groups using a log-rank test. The energy required for dose-response and concentration-response correlation and DC conversion is tested using descriptive statistics. Subjects with atrial fibrillation and atrial flutter are analyzed separately. In addition, the dual population is pooled for analysis. All analyzes including the atrial flutter target population will be considered as examinations.

  From these data, male patients with antiarrhythmia are more likely to be at tedisamil than female patients in antiarrhythmic treatment, and particularly in the conversion of the recent onset of atrial fibrillation (Afib) / coarse to normal sinus rhythm (NSR). It can be seen that it responds more specifically to the treatment.

  As indicated by the results of the test, 3,7-diazabicyclo [3.3.1] -nonane compound, preferably 9,9-alkylene-3,7-diazabicyclo [3.3.1] -nonane compound, and Most advantageously in the treatment and / or prevention of antiarrhythmic events in male patients, particularly in male patients with atrial flutter (Afib), in male patients of tedisamil, its pharmaceutically acceptable acid addition salts and / or solvates The effect on the recent pathogenesis conversion to NSR is particularly surprising since no gender difference in terms of such effect has been previously observed in various treatments with tedisamil in both sexes.

  From the results regarding the effect of tedisamil found in the test, it was found that the tedisamil-like 3,7-diazabicyclo [3.3.1] -nonane compound, preferably 9,9-alkylene-3,7-diazabicyclo [3.3.1]. It can be summarized that nonane compounds, and most advantageously tedisamil itself, as well as acid addition salts, show higher conversion rates in male patients compared to female patients. When the injection was extended beyond the above time, no higher conversion was shown. From this result, safety can be summarized as follows: Almost all TdP (torsade de pointe) observed in the 30-minute method was in female patients. Only one man showed TdP at a high dose of 0.72 in the test.

Liquid pharmaceutical compositions 3,7-diazabicyclo [3.3.1] -nonane compounds, preferably 9,9-alkylene-3,7-diazabicyclo [3.3.1] -nonane compounds, and most as therapeutic agents Advantageously, any conventional and / or newly developed pharmaceutical formulation component suitable for use in intravenous injection and infusion with tedisamil and its pharmaceutically acceptable acid addition salts and / or solvates, For example, it may be contained in a liquid pharmaceutical composition according to the present invention together with excipients, liquid carriers, auxiliaries, and / or adjuvants. Examples of liquid compositions are in particular 3,7-diazabicyclo- [3.3.1] -nonane compounds, preferably 9,9-alkylene-3,7-diazabicyclo [3.3.1] -nonane compounds, and Most advantageously a liquid, suspension or emulsion suitable for intravenous injection or for infusion of tedisamil and of its pharmaceutically acceptable acid addition salts and / or solvates and / or prodrugs , Liposomes, solid lipid nanoparticles, and any other conventional and / or novel drug delivery systems. Infusions are, for example, sterile aqueous solutions or emulsions with water as a continuous phase; these are usually made isotonic with blood. These are scheduled for administration in large volumes in principle.

  Liquid compositions can usually contain diluents such as water, oils and / or lipids, organic solvents or cosolvents, suspending agents and the like. Other conventional and / or novel auxiliaries which are likewise suitable for use in intravenous injection and in particular infusion can additionally be added, eg preservatives, stabilizers, antioxidants, pH adjustment Agents, buffers, such as adjuvants for tonicity adjustment or viscosity adjustment, antibacterial and / or antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid and the like can be added. Advantageously, the liquid pharmaceutical composition is suitable for infusion methods, for example intravenous infusion. The ingredients, techniques, and methods required for active pharmaceutical liquid pharmaceutical compositions are well known to those skilled in the art.

  Of 3,7-diazabicyclo- [3.3.1] -nonane compounds, preferably 9,9-alkylene-3,7-diazabicyclo [3.3.1] -nonane compounds, and most preferably of tedisamil, and The pharmaceutically acceptable acid addition salts and / or solvates and / or prodrugs can be mixed and molded with pharmaceutical excipients, auxiliaries, liquid carriers and / or adjuvants in a known manner. For example, the active compound and the required liquid pharmaceutical excipient or carrier and ingredients such as desired auxiliaries and adjuvants are mixed together, optionally lyophilized, and the resulting solution, emulsion or liposome, for example, Suitable primary packaging materials, such as vials, ampoules, containers, injection pouches or dual chamber systems suitable for injection purposes, can be filled and additionally sterilized. Usually, the infusion solution must be prepared very carefully; in particular the solution must be isotonic or at least nearly isotonic. The pH value is usually adjusted by adding hydrochloric acid or sodium hydroxide. The infusion should be isotonic or nearly isotonic, for example isotonic or nearly isotonic. For example, sodium chloride, glucose or mannitol can be added in order to make a low osmotic pressure solution an isosmotic condition. In some cases, compromises are needed regarding isotonic conditions, normal body water conditions, physiological needs, and active agent stability. Stabilization and / or sterilization is preferred. In the manufacture of infusion solutions containing dispersed particles, measurements are carried out to ensure a suitable and controlled particle size in view of the intended use. The volume of infusate in the container is sufficient to allow withdrawal and administration of standard doses using standard techniques. Suitable methods, components and conditions to be combined for producing infusion solutions are well known to the person skilled in the art, for example from research articles and / or pharmacopoeias such as the European or US pharmacopoeia.

  According to a particular aspect of the present invention, liquid medicaments are suitable for administration by infusion, especially for intravenous administration. Those skilled in the art will know how to make infusion solutions and / or intravenous injection solutions, what conditions should be met, and how infusion solutions should be administered to patients. I know. Infusion solutions can be prepared from injections or concentrates for infusion. A concentrate for injection or infusion is a sterile solution for injection or infusion after dilution. This is diluted to the prescribed volume with the prescribed liquid prior to administration. After dilution, this meets the requirements for injection or infusion. Infusions can also be prepared from solid powders for injection or infusion that are dissolved in the required amount of a suitable sterile solvent just prior to administration to a patient. Powder for injection or infusion is a solid sterilized substance that is dispensed in the final container, which is rapidly clear and substantially clear when shaken with the prescribed volume of the prescribed sterile solution. To form a particle-free solution or a heterogeneous suspension. After lysis or suspension, they fully meet the requirements for injection or infusion. Usually lyophilized products for parenteral use are considered as powders for injection or infusion.

  Intravenous administration allows for rapid administration of large volumes. The advantage of infusion is, for example, the rapid onset of the pharmacological effect of the active agent, especially in emergency situations. For example, the infusion can be administered as a rapid infusion during the first phase or phase of administration, and then a constant blood concentration of the drug can be achieved and / or maintained over the period of administration. Intravenous administration by infusion is performed. Administration is also possible in a dual chamber system to avoid drug instability prior to administration.

Examples The following examples also describe liquid pharmaceutical compositions containing an active substance of formula I according to the present invention and the preparation of such pharmaceutical formulations. The following example illustrates the preparation of a liquid pharmaceutical formulation containing tedisamil dihydrochloride. A liquid pharmaceutical formulation containing teddysamil sesquifumarate can be obtained in a similar manner.

Example: Ampoule composition (per ampoule)
N, N'-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane dihydrochloride 5 mg
Sodium chloride 16mg
Bring to 2.0 ml with water for injection.

Preparation Method Sodium chloride was dissolved in water for injection. The active substance is added and dissolved under stirring. Sufficient water for injection purposes was added to the final volume. The mixture was passed through a 0.25 μ membrane filter. A 2.15 ml portion was filled into a brown glass ampoule and the ampoule was sealed airtight. The ampoule was sterilized with 121 DEGC for 30 minutes with steam. The resulting 2 ml of injection solution contains 5 mg of active substance.

The figure which shows the flowchart of a test | inspection.

Claims (20)

  A therapeutically effective amount of at least one 3,7-diazabicyclo [3.3.1] nonane compound, at least one of its physiologically acceptable acid addition salts and / or solvates and / or prodrugs. Fluid for the treatment and / or prevention of anti-arrhythmic events in human patients, preferably in the conversion of recent atrial fibrillation (Afib) or flutter in human patients to normal sinus rhythm (NSR) Pharmaceutical composition, suitable for staged administration, totally discontinuous administration and / or optionally only partly continuous administration, preferably in two consecutive administration phases Liquid pharmaceutical composition that is suitable for two-stage administration.   This liquid pharmaceutical composition is for infusion administration, preferably for step-by-step infusion administration, optionally with each step being partly continuous infusion administration, preferably two-stage infusion of two continuous infusion administration phases 2. The liquid pharmaceutical composition according to claim 1, which is suitable for administration. The 3,7-diazabicyclo [3.3.1] nonane compound has the formula I:

[Where:
R1 is an alkyl group having 1 to 6 carbon atoms, a double bond not directly bonded to a nitrogen atom, an alkylene group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 4 to 9 carbon atoms Or represents a benzyl group,
R2 represents a lower alkyl group and R3 represents a lower alkyl group, or R2 and R3 together form an alkylene chain having 3 to 6 carbon atoms, and R4 is 1 to 6 carbon atoms An alkenyl group having 3 to 6 carbon atoms, a cycloalkylalkyl group having 4 to 9 carbon atoms, a double bond not directly bonded to a nitrogen atom, a formula a:

(Wherein R5 represents a hydrogen, halogen, lower alkyl or lower alkoxy group, and Z represents an alkylene chain having 1 to 3 carbon atoms, or a propenylene having a double bond conjugated to a phenylene group. Or a group corresponding to formula b:

Wherein R6 represents a hydrogen, halogen, lower alkyl or lower alkoxy group, and R7 represents a hydrogen, halogen, lower alkyl or lower alkoxy group. 3. A liquid pharmaceutical composition according to claim 1 or 2 which is a pharmaceutically acceptable acid addition salt and / or solvate and / or prodrug.   4. The liquid pharmaceutical composition according to claim 3, wherein R1 represents an alkyl group having 1 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms.   4. A liquid pharmaceutical composition according to claim 3, wherein R4 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkylalkyl group having 4 to 7 carbon atoms or a group corresponding to formula b.   In the formula, R1 represents an alkyl group having 3 to 6 carbon atoms or a cycloalkylalkyl group having 4 to 7 carbon atoms, and R4 represents an alkyl group having 3 to 6 carbon atoms or 4 to 7 carbon atoms. The liquid pharmaceutical composition according to claim 3, which represents a cycloalkylalkyl group having   The 3,7-diazabicyclo [3.3.1] nonane compound forms an alkylene chain having 4 to 5 carbon atoms, together with R2 and R3 in Formula I, wherein R1 and R4 are independent of each other. A 9,9-alkylene-3,7-diazabicyclo of formula I representing a straight-chain or branched alkyl group having 3 to 4 carbon atoms or a cyclopropylmethyl group [3.3.1] 4. A liquid pharmaceutical composition according to claim 3, which is a nonane compound and physiologically acceptable acid addition salts and / or solvates and / or prodrugs thereof.   9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compound wherein the 3,7-diazabicyclo [3.3.1] nonane compound has 1.5 moles of fumaric acid per mole of the compound of formula I The liquid pharmaceutical composition according to claim 7, which is a fumarate salt.   3,7-diazabicyclo [3.3.1] nonane compound is N, N′-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane, N-isobutyl- N'-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3.3.1] nonane compound and its physiologically tolerable acid addition salts and / or solvates and / or prodrugs The liquid pharmaceutical composition according to claim 3, which is selected from:   3,7-diazabicyclo [3.3.1] nonane compound is N, N′-dicyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane, or N— Isobutyl-N'-isopropyl-9,9-pentamethylene-3,7-diazabicyclo [3.3.1] nonane, said 9,9-alkylene-3,7-diazabicyclo [3.3.1] nonane compound The liquid pharmaceutical composition according to claim 9, which is a fumarate salt containing 1.5 mol of fumaric acid per mol.   The liquid pharmaceutical composition according to any one of claims 3 to 7 and 9, wherein the 3,7-diazabicyclo [3.3.1] nonane compound is a hydrochloride.   About 10 ± 2 minutes, preferably about 10 ± 1 of 3,7-diazabicyclo [3.3.1] nonane compound, physiologically tolerable acid addition salts and / or solvates and / or prodrugs thereof Containing a first therapeutically effective amount that is sufficient for the treatment and / or prevention of anti-arrhythmic events in human patients over a first time period of minutes, most advantageously about 10 ± 0.5 minutes. And treatment and / or prevention of 3,7-diazabicyclo [3.3.1] nonane compound, its physiologically acceptable acid addition salts and / or solvates and / or prodrugs for about 20 ± 5 minutes Any one of claims 1 to 11, containing a second therapeutically effective amount, preferably sufficient to continue over a second time period of about 20 ± 3 minutes, most preferably about 20 ± 1 minutes A liquid pharmaceutical composition according to claim 1.   In a method for the treatment and / or prevention of an antiarrhythmic event in a human patient, preferably in a method in the conversion of an atrial fibrillation (Afib) or flutter in a human patient to normal sinus rhythm (NSR) A liquid pharmaceutical composition comprising a therapeutically effective amount of one 3,7-diazabicyclo [3.3.1] nonane compound or a physiologically tolerable acid addition salt and / or solvate and / or prodrug thereof Administered to the human patient by a stepwise route of administration, a totally discontinuous route of administration and / or optionally only a partially continuous route of administration, preferably for a two-step administration of two successive administration phases A method of treating and / or preventing an antiarrhythmic event in a human patient.   Infusion administration of a liquid pharmaceutical composition containing a therapeutically effective amount of a 3,7-diazabicyclo [3.3.1] nonane compound, or a physiologically tolerable acid addition salt and / or solvate and / or prodrug thereof 14. Treatment according to claim 13, wherein the treatment is preferably by gradual infusion administration, optionally each stage is partly continuous infusion administration, preferably for two-stage administration of two consecutive administration phases. And / or prophylaxis.   3,7-diazabicyclo [3.3.1] nonane compound, physiologically tolerable acid addition salts and / or solvates and / or prodrugs thereof for the treatment and / or prevention of antiarrhythmic events in human patients A first therapeutically effective amount sufficient for the treatment of 3,7-diazabicyclo [3.3.1] nonane compound, physiologically tolerable acid addition salts and / or solvates and / or prodrugs thereof, and A liquid pharmaceutical composition containing a second therapeutically effective amount that is sufficient to continue prophylaxis is obtained by applying a first effective amount of about 10 ± 2 minutes, preferably about 10 ± 1 minutes, most preferably Administered over a first time period of about 10 ± 0.5 minutes and a second effective amount for a second time of about 20 ± 5 minutes, preferably about 20 ± 3 minutes, most preferably about 20 ± 1 minutes 14. Administered over a band Or the treatment and / or prevention method according to 14.   12. At least one 3,7-diazabicyclo [3.3.1] nonane compound, physiologically acceptable acid addition salt thereof and / or as defined in any one of claims 3 to 11 Alternatively, a therapeutic and / or prophylactic method according to any one of claims 13 to 15, wherein a therapeutically effective amount of a solvate and / or prodrug is administered.   12. At least one 3,7-diazabicyclo [3.3.1] nonane compound, at least one physiologically acceptable acid thereof, as defined in any one of claims 3-11. A therapeutically effective amount of an addition salt and / or a solvate and / or a prodrug is included in the liquid pharmaceutical composition as a drug, and the 3,7-diazabicyclo [3.3.1] nonane compound is added step by step. Label, leaflet and / or package indicating that it can be administered discontinuously and / or optionally only partly continuously, preferably for two-stage administration of two consecutive administration phases A pharmaceutical product and / or package containing a charge.   The label, leaflet and / or package charge is preferably a liquid pharmaceutical composition for infusion administration, preferably for stepwise infusion administration, optionally with each stage being partially continuous infusion administration, 18. A pharmaceutical product and / or package according to claim 17 outlined in that it is suitable for a two-stage infusion administration of two consecutive infusion administration phases.   Label, leaflet and / or package charge of 3,7-diazabicyclo [3.3.1] nonane compound, physiologically tolerable acid addition salts and / or solvates and / or prodrugs thereof A first therapeutically effective amount sufficient for the treatment and / or prevention of an antiarrhythmic event in a patient and said 3,7-diazabicyclo [3.3.1] nonane compound, a physiologically tolerable acid addition salt thereof And / or a liquid pharmaceutical composition containing a second therapeutically effective amount of the solvate and / or prodrug that is sufficient to continue treatment and / or prevention, the first effective amount is about 10 ± 2 minutes. Administered over a first time period of preferably about 10 ± 1 minutes, most preferably about 10 ± 0.5 minutes, and the second effective amount is about 20 ± 5 minutes, preferably about 20 ± 3 minutes, Most advantageously about 19. Outlined that a 3,7-diazabicyclo [3.3.1] nonane compound can be administered according to a dosing regimen of administering over a second time period of 0 ± 1 minutes. Pharmaceutical products and / or packages.   12. A liquid pharmaceutical composition as drug, at least one 3,7-diazabicyclo [3.3.1] nonane compound, as defined in any one of claims 3-11, physiologically 20. A pharmaceutical product and / or package according to any one of claims 17 to 19, comprising a therapeutically effective amount of an acceptable acid addition salt and / or solvate and / or prodrug.

Images